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Process for Producing Aliprazo

A technology based on piperazinyl and general formula, which is applied in the field of preparation of aripiprazole, can solve problems such as multiple side reactions, many side reactions, and reduced total yield, and achieve strong reaction specificity, simple post-treatment, and low by-product production. little effect

Inactive Publication Date: 2005-02-09
重庆凯林制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because 1,4-dibromobutane will undergo hydrolysis reaction in this reaction system, and there are many side reactions in this reaction; Intermediate (I) purification is more difficult, and its quality is difficult to guarantee
[0006] The impurities introduced by the intermediate will affect the next reaction, and the introduced impurities are also difficult to remove by conventional recrystallization methods, and the quality of the finished product is difficult to guarantee
If it is necessary to obtain aripiprazole with "pharmaceutical grade" purity, the obtained crude aripiprazole with a purity of only 94% must be purified by repeated recrystallization (or column chromatography) to obtain "drug grade". "grade" aripiprazole, the total yield is greatly reduced
Even if the product quality can be guaranteed, it is extremely unfavorable for the industrialized production of the product
[0007] And the other four methods for preparing aripiprazole only described in the claims, because of involving the preparation of piperazine ring, are more unfavorable for the industrialization of products, because when carrying out the preparation of piperazine ring, the reaction temperature is higher than 220 ℃, many side reactions and extremely low yield

Method used

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  • Process for Producing Aliprazo
  • Process for Producing Aliprazo
  • Process for Producing Aliprazo

Examples

Experimental program
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Effect test

preparation example Construction

[0045] One, the preparation of compound (C): (F)+(E)—→(C)

[0046] 4-[4-(2,3-dichlorophenyl) piperazinyl]-1-butanol (C) can be by 1-(2,3-dichlorophenyl) piperazine (E) and general formula ( A compound of F) is reacted in a solvent at a temperature ranging from room temperature to 200°C, preferably 80-140°C, and the reaction is completed within a few hours to 48 hours. As for the solvent used in this reaction, it can be the following solvents, ether solvents such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene, toluene, pyridine, xylene; alcohol solvents such as Methanol, ethanol, isopropanol; aprotic solvents such as N,N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, acetonitrile. Use of a basic reagent facilitates the reaction. Said alkaline reagent can be potassium hydroxide, potassium carbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium amide, sodium hydride inorganic base, or ...

example 1

[0055] Preparation of 4-[4-(2,3-dichlorophenyl)piperazinyl]-1-butanol (C)

[0056] Put 5.80g (25mmol) of 1-(2,3-dichlorophenyl)piperazine (E), 3.3g (30mmol) of 4-chloro-1-butanol, and 4.15g (30mmol) of potassium carbonate into the reaction flask successively. ), acetonitrile 25ml, a little potassium iodide, heated and refluxed for 26 hours under stirring, after the reaction was completed, suction filtered, removed inorganic matter, filtered and washed, concentrated the filtrate, recovered part of the organic solvent, added 30ml of ethyl acetate and 10ml of distilled water to the concentrate , separate the organic layer, extract the aqueous layer three times with 10ml ethyl acetate, combine the organic layers, wash with 20% saline until neutral, dry the organic layer with anhydrous sodium sulfate, filter with suction, filter off the desiccant, and recover the organic layer under reduced pressure. solvent. Add 5ml of ethyl acetate to the residue, adjust PH=5 with hydrochloric a...

Embodiment 2-6

[0081] Preparation of 4-[4-(2,3-dichlorophenyl)piperazinyl]-1-butanol (C)

[0082] Dissolve 1-(2,3-dichlorophenyl)piperazine (E) and 4-chloro-1-butanol (F) in the following solvents, respectively use corresponding acid removal agents, heat and keep warm for reaction. After the reaction is completed, it becomes hydrochloride after being processed, and the obtained salt is free into free base (C) after recrystallization, as shown in Table 1:

[0083] Example Solvent Deacidifier Temperature (°C) Time (h) Yield (%)

[0084] 2 Isopropanol Potassium hydroxide 70 30 43.8

[0085] 3 Toluene Triethylamine 100 20 72.5

[0086] 4 THF / DMSO Potassium hydroxide 50 18 69.2

[0087] 5 N,N-Dimethylformamide Potassium carbonate 90 24 61

[0088] 6 Acetonitrile Pyridine 75 30 48.7

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PUM

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Abstract

The present invention relates to the preparation process of Aripiprazole. Aripiprazole is prepared with two kinds of compound and through condensation. The preparation process of the present invention has mild reaction condition, less side products, simple operation and controllable quality of the intermediate, and the Aripiprazole product of the present invention may reach relevant medicine standard without needing several times of re-crystallization.

Description

technical field [0001] The present invention relates to aripiprazole (7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro- 2(1H)-quinolinone) preparation method. Background technique [0002] As we all know, aripiprazole is a quinolinone derivative, which was invented by Otsuka Corporation of Japan in 1988, and then jointly developed with Bristol-Myers Squibb Corporation of the United States. It was approved for marketing by the FDA in 2002. For the treatment of schizophrenia. [0003] Regarding the preparation of aripiprazole, five preparation methods described in the EP367141 patent are known. The specification of this patent describes one of the methods for preparing aripiprazole. The synthetic route is to use 7-hydroxy-3,4-dihydro-quinolin-2-one as raw material, and 1,4-di Bromobutane makes 7-bromobutoxy-3,4-dihydro-quinolin-2-ketone (I) after condensation reaction, and (I) is mixed with 1-(2,3-dichlorophenyl) Aripiprazole is obtained by condensation react...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/227
Inventor 诸葛明邓杰叶文润张国尧邢乃果
Owner 重庆凯林制药有限公司
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